Published in the September 2010 issue of Today’s Hospitalist
When it comes to treating patients with HIV/AIDS, recommendations on when to start antiretrovirals continue to change while the number of available drugs and drug combinations keeps surging up. For physicians who treat HIV/AIDS patients, those converging trends raise two key questions.
One has to do with the timing of therapy. The latest practice guidelines urge physicians to start HIV/AIDS therapy sooner rather than later to not only help individual patients, but reduce disease transmission. But physicians on the frontlines of HIV care can be confused about when exactly to start therapy.
And because there are now so many therapies to choose from, there’s an even bigger issue: Has HIV care become a field like oncology, where only very specialized individuals should make choices about which drugs to use?
“Is this something that internists and hospitalists should be part of?” asked Henry Masur, MD, chief of clinical care medicine for the National Institutes of Health in Bethesda, Md., speaking at this spring’s Society of Hospital Medicine’s annual meeting.
The challenge of choice
The last two decades haven’t merely seen the development of more HIV/AIDS drugs. They’ve also brought dramatic improvements in how well these drugs work.
In some early antiretroviral trials, for instance, “only 40% of the patients were successful,” Dr. Masur explained. “Now we are seeing trials where 90%, 95%, 97% of therapies are a success in terms of suppressing viral activity and extending life.”
In all, more than two dozen drugs in six different categories have been approved over the past 20 years by the FDA for people with HIV and AIDS. The new drugs are more effective, less toxic and more lipid-sparing. They are also much less likely to cause fat redistribution, and they make it possible for patients to take just one or a few pills a day, not a handful.
While the wave of new therapies is good news, the task of keeping current with guideline recommendations can be overwhelming. “It’s very easy to get behind the curve in terms of what the recommended regimen is,” Dr. Masur said. “If you are going to make appropriate decisions about what drugs to use and what drugs to change, either you have to practice HIV medicine on a regular basis or refer to someone who does and who keeps up on the literature.”
Timing therapy
Complicating the decision-making process is another basic fact: As the number of HIV/AIDS drugs has risen, more and more evidence indicates that patients benefit from earlier therapy, before their CD4 count falls to 350 or 200 cells/uL.
Based in part on established research demonstrating that earlier treatment is more effective, the federal government’s December 2009 guidelines now say that physicians should treat people with CD4 counts of between 200 and 350. In other words, doctors shouldn’t wait until patients have AIDS-defining disease to begin therapy. (The 2009 guidelines for adults, as well as up-to-date information on many aspects of HIV/AIDS care, can be found at www.aidsinfo.nih.gov.)
“We know that if you start therapy earlier, you will ultimately get to a better CD4 count,” said Dr. Masur. “We can debate whether a CD4 count of 600 is better than 400, but you clearly get a better immunological outcome.”
He also pointed to growing evidence that antiretroviral therapy helps patients whose CD4 counts are greater than 350. Another big reason to start antiretrovirals early: Research has now shown that many of the toxicities associated with these drugs are more likely to kick in when CD4 counts dip near 100, rather than when they stay in the 400 to 500 range.
Finally, Dr. Masur explained, guidelines also call for earlier initiation of antiretrovirals because there are so many more treatment options if the first regimen fails.
“The fear of losing the opportunity for successful therapy is mitigated, to a degree, by the fact that there are now drugs with different mechanisms of action,” Dr. Masur said. “If one regimen fails, another can be tried “although no regimen should be recommended if the patient is not ready to make a strong effort to adhere.”
Resistance still a problem
Even with the wave of new HIV/AIDS drugs, Dr. Masur pointed out, an old issue continues to rear its ugly head: resistance. The rate of patients who have never taken antiretrovirals but have resistance runs between 5% and 8%, he said, depending on the drug.
And as patients are treated, “resistant virus can be transmitted to their previously uninfected sexual or needle sharing partners,” Dr. Masur pointed out. Fortunately, patients with a resistant virus “or a high likelihood of having resistance to multiple drugs “can be treated with newer drugs that to date show little resistance in the community. Integrase inhibitors, for example, are a relatively new class of drugs that “offer considerable efficacy for patients with resistance to the drugs that have been in use for longer periods of time.”
Opportunistic infections
How do all of these developments affect physicians? While many hospitalists may defer to infectious disease specialists in terms of choosing antiretrovirals, Dr. Masur said that hospitalists clearly have a role in managing patients both before and after they start therapy.
A dilemma that hospitalists regularly encounter, he said, is what to do with a patient hospitalized with an HIV-related opportunistic infection, such as crytococcal meningitis or pneumocystis pneumonia, who has never taken antiretrovirals.
The old approach, he explained, was to defer antiretroviral therapy until after the patient recovers from the infection and can start treatment as an outpatient. New studies, however, find that starting antiretrovirals earlier rather than later, even for this population, is a better way to go.
“The problem, of course, is defining how early,” Dr. Masur noted. Physicians should avoid ordering antiretrovirals in the first few days because of concerns about overlapping toxicities, drug absorption and the resistance associated with suboptimal absorption.
While experts have reached no consensus as to when exactly to start antiretroviral therapy with a recently diagnosed opportunistic infection, he said, “the preference is to start earlier rather than wait until after hospital discharge.”
Stopping and starting antiretrovirals
As for caring for hospitalized patients already taking antiretrovirals, Dr. Masur said that it’s sometimes just easier to stop therapy temporarily. That’s particularly true for patients in the ICU who are subject to “a very confusing number” of drug interactions, he noted, and to uncertain drug absorption, given the fact that almost all of these agents are oral.
Likewise, deciding when to re-start therapy “really depends on what other drugs patients need to be on,” Dr. Masur said, adding that he’s not concerned about resistance in temporarily halting antiretroviral therapy. “Resistance is caused by suboptimal levels that occur due to poor absorption, changing volumes of distribution or unrecognized drug interaction.”
Hospitalists also need to know, he added, that just because a patient comes in with an opportunistic infection within 12 weeks of starting therapy, that doesn’t automatically mean that the antiretroviral therapy has failed and should be switched.
Instead, said Dr. Masur, look at the viral loads and CD4 counts. There is no evidence that switching antiretroviral therapy will improve outcomes or the CD4 count in a patient who has achieved a viral load of less than 50 copies.
Preventing infections
In terms of preventing opportunistic infections, Dr. Masur stressed the need for chemoprophylaxis against pneumocystis, toxoplasma, M. avium, and ” for patients living in the Southwest “coccidiomycosis. Chemoprophylaxis should continue until patients’ CD4 count rises. (The exact threshold when chemoprophylaxis should be stopped depends on the pathogen and can be found in a table in the opportunistic infection guidelines at www.aidsinfo.nih.gov.)
Hospitalists also need to tell patients to have their CD4 counts checked at least every month for the first three months of therapy. The idea is to see if patients are responding appropriately, have a resistant virus, or aren’t compliant or are experiencing a drug interaction.
Monthly visits, moreover, said Dr. Masur, allow more teaching and can lead to better understanding of how to manage the disease. “A lot of the dialogue you have with patients is very important for their long-term success, he said. “They have to understand the drug and have realistic information about toxicity. And if they are not going to take the drugs, it’s better to stop them rather than take them intermittently.”
Deborah Gesensway is a freelance writer based in Toronto who covers U.S. health care.
HIV: Is it time for universal screening?
WITH HIV/AIDS continuing to be a major public health crisis in the U.S., some experts strongly advocate for universal, voluntary screening, and then for giving antiretrovirals to patients found to be infected.
That way, the thinking goes, the U.S. may finally start making a dent in the constant rate of new infections “more than 56,000 a year “that has held steady for 20 years. While the disease “remains a major problem within the white gay population,” said Henry Masur, MD, chief of clinical care medicine for the National Institutes of Health in Bethesda, Md., “HIV has now shifted to being an inner-city black disease.” That’s particularly the case in Washington, D.C., and other urban centers.
As for universally screening all patients who enter the hospital, Dr. Masur said the cost effectiveness of such a policy depends on where you practice. The Cleveland Clinic, for instance, is now phasing in universal testing for all patients. Because the hospital is in metropolitan Cleveland, that strategy may “have a high yield.”
But even in areas with high rates of HIV infection, not all hospitals or emergency rooms are equipped to do either rapid testing or appropriate follow-up for patients with positive results. Instead, communities need to assess different screening strategies.
“Universal testing in some cities might be better done door-to-door in targeted high-risk areas,” said Dr. Masur, “or telling HIV-infected patients to bring in five friends.” As for hospital screening policies, he added, “there isn’t any one approach that fits all.”
The history of HIV drug development
SINCE AZT FIRST ARRIVED on the scene in 1987, scientists have learned much about the need to move from single nucleoside therapy to combination therapy to achieve sustained virologic response. In addition, more effective and less toxic nucleosides have been developed.
“The initial strategies focused on the nucleosides that had very short-term effects, so we wanted to wait and use them only when patients absolutely needed them,” said Henry Masur, MD, chief of clinical care medicine for the National Institutes of Health in Bethesda, Md. Dr. Masur spoke about HIV care at this spring’s Society of Hospital Medicine’s annual meeting.
Initial HIV drugs quickly developed resistance, he pointed out, and had “major toxicities” associated with them, including hepatic steatosis, lactic acidosis and peripheral neuropathy. That often dampened both patients’ and physicians’ enthusiasm for the drugs.
While that first wave of HIV/AIDS treatment was characterized as reserve therapy, the next evolution focused on how to reduce both short- and long-term toxicities of the drugs “and drug combinations “that had proven to be effective.
“As the drugs became available,” said Dr. Masur, “many people in the field of HIV medicine became convinced that they knew how best to treat patients without doing clinical trials.”
He offered himself as a cautionary example: He was one of many HIV experts who was sure the way to reduce the costs, adherence problems and toxicity of therapy was to simply give the drugs intermittently, he said. They then learned, however, “that often we don’t know as much as we think.”
In a landmark study in the Nov. 30, 2006, issue of the New England Journal of Medicine, the authors found “clear and compelling evidence that the episodic antiretroviral strategy “¦ is deleterious” and led to “significantly increased “¦ risk of opportunistic disease or death from any cause.”
Where are we now in terms of the evolution of HIV care? Chastened HIV medicine experts have a large arsenal of drugs to draw from, Dr. Masur pointed out, but each of the drugs “will have toxicity if you look at a large enough patient population over a long enough period of time. The question in 2010 is: How do we use all these drugs?”
Despite what he called “tremendous progress,” Dr. Masur said, researchers need to continue studies to understand the pathophysiology of disease and determine optimal treatment strategies.
“With new drugs and more patients surviving more years,” he noted, “we have much more to learn to minimize the effect of HIV infection on patient quality of life and longevity.”
